Immunotherapy of Cancer With Monoclonal Antibodies
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Immunoglobulin's are mainly useful in developing antibodies to the antigen which entered into the body and creating immunological disturbances are been lysed. Similarly, Monoclonal antibodies are useful in treating the cancer which is developed from monoclonal hybridomas. These monoclonal antibodies or hybridomas are produced by fusion of antibody producing cells with non-immunoglobulin tumors cells for lysing the cancerous cell. It can lyse or kill the tumors cells by various methods like antibody dependent cell mediated cytotoxicity, blocking the receptors or by inducing apoptosis cell death and the developing tumor can be inhibited. Mainly here we will be discussing the development, mechanism of action and various technique or methods used for production of monoclonal antibodies and their action on lymphocytic myeloma by using one of the ways of mechanism of action to produce immunotherapy of cancer with monoclonal antibodies.
Monoclonal antibodies are showing various positive effects when treated against the tumor cells by various ways of mechanisms. They act by inducing apoptosis or initiating the cell lysis by various cell lysis processes which is programmed generally in the cell if it has been infected by cytotoxicity, blocking growth factors which are mainly involved in cell growth, by complement activation. In cytotoxicity of cell involves stimulating the cells like monocytes, macrophages etc., and producing antibodies against the tumor cells which act as antigens to the antibodies produced by macrophages, monocytes induced by monoclonal antibodies stimulation. Monoclonal antibodies even act by stimulating cytotoxicity by stimulating the complement system and causing cell toxicity leading to cell death. They even block the growth of the tumor cells by blocking the growth factor receptors and arresting the proliferation of the tumor cells. Even natural killer cells act by stimulating the complement system the various examples which are included in the cell lysis. Rituximab is IgG monoclonal antibody, which has an Fc receptor. The rituximab fc fragment bind to the fc receptors in monocytes, natural killer cells etc., these cells get stimulated and engulf the tumor cells which are bound to the receptors either by MHC-1 or 2. An example for complement system cytotoxicity is by using B cell lymphoma where we can see these antibodies bind to the receptor and activating the complement system following the result of cell lysis by making holes into the cells and lysing it causing the death the tumors cells.
GOALS OF STUDYING MONOCLONAL ANTIBODIES:
The specific goals used in treating cancer with monoclonal antibodies are
- Antibody Dependent Cellular Cytotoxicity (ADCC) and its role in anti-tumor efficacy of tumor antigen-specific antibodies
- Monoclonal antibodies are used as adjuvants in developing adaptive immunity
- Balance the activating and inhibitory Fc receptors on the outcome of antigen presentation
- Using of anti-idiotypic antibodies as miming agents and triggering of the idiotypic complement cascade by antibody-based immunotherapy.
In antibody dependent cellular toxicity (ADCC) the monoclonal antibodies which are obtained from the hybridomas cells (which formed due to the fusion of immunoglobulin producing antibody and the non-immunological cancer cells resulting in antibody producing myelin cells to similar the specific myelin cells) where these antibodies go and bind to the tumor cell antigen.by the attachment of these antibodies to the tumor cells helps in attracting Nk cells. The tumor cell will get lysed which there is fusion of fc receptor of Nk cells and fc portion of antibodies mediating the release of endotoxins which lyse the specific tumor cells. Similarly in the complement dependent cytotoxicity these monoclonal antibodies bind to the receptors and initiate complement system resulting into the complement cascade which cause hole in the cells and leading to cell death.
Now a day the monoclonal antibodies are used in developing the adaptive immunity by attaching themselves with the dendritic cells and producing antibodies to the specific antigen in the body and developing and memory cells against the specific cancer cells by stimulating the T cells. The dendritic cells which are in inactivated stage in the absence of external stimulus can be activated only when inhibitory fcγ receptors are avoided. Then these enter into maturation phase and start producing immunity by activating T cells and other cells. This can be achieved only when the monoclonal antibodies inhibit the specific inhibitory factors which are inhibiting DC cells.
The heavy and light chains which are available in the immunoglobulin's will be having the complimentary sequence which is opposite to the antigen of the pathogens or other resulting in activation of immune system in deactivating it by lysis or causing the death of the organism. Some idiotopes are located in the antigen binding site of the antibody which interacts with the corresponding antigen. According to the Jerne's theory, stimulation of antibody causes the idiotypic cascade leading to the cell lysis and referred as anti-idiotypic antibodies.
IMPORTANT METHODS USED IN PRODUCTION AND DETECTING THE TUMOR CELLS
Production of monoclonal antibodies involves five steps:
1) Immunization of Mice and selection of donors for Generating of Hybridoma Cells:
Mice are firstly immunized with antigen and kept for 2-3 weeks to obtain desired number of antibodies against the antigen. The amount of antibodies which we desire can be determined by measuring the serum of the mice.
2) Screening the Mice for Antibody Production:
To know the amount of antibodies required for production of monoclonal antibodies can be determined with the ELISA (enzyme linked immunosorbent assay) and flow cytometry. If the production or the antibody number is high we can perform cell fusion if not we have to boost the mice with more antigen. If the antibody production is high we remove the spleen from the mice and production hybridoma cell production.
3) Preparation of Myeloma Cells before fusion:
Fusion of antibody producing spleen cells and with those cells which are derived from immortal tumor lymphocyte myeloma cells which results in production of hybridoma cells that are capable of unlimited growth. Myeloma cells are immortal cells that are cultured with 8-azaguanine to ensure that they are sensitive to the hypoxanthine-aminopterin-thymidine (HAT) selection medium which is used after the cell fusion.
4) Fusion of Myeloma Cells with antibodies producing Spleen Cells:
Fusion of myeloma cells with that of antibody producing spleen cells in the presence of polyethylene glycol which helps in fusion of membranes. And the cells which undergo fusion only will be growing in HAT medium. The produced hybridoma cells are screened and purified which are able to produce antibodies against the specific lymphocyte myeloma cells in the human body are multiplied through transformation to obtain the fusion cell which is have the capability of producing antibodies or immunoglobulin and express myeloma character i.e., Rituximab is monoclonal antibody which mainly targets the CD20 antigen which is expressed only on B cell malignancies. It's an IgG monoclonal antibody which has an fc receptor. The fc fragment of the Rituximab binds to the fc receptors found on monocytes, macrophages and Nk cells. immortal.
MOST IMPORTANT FINDINGS OF MONOCLONAL ANTIBODIES IN IMMUNOTHERAPY OF CANCER:
The 'US FOOD AND DRUG ADMINISTRATION' approved twenty one monoclonal antibody products. Rituximab is the first monoclonal antibody which was first approved cancer treatment. In addition to this 6 unconjugated monoclonal antibody one drug immunoconjugate, 'Gemtuzumab', 'Ozogamicin' has been approved. These humanized monoclonal antibodies CD33 used to treat acute myelogenous leukemia and use of the antibodies which are conjugated to calicheamicin. Unlike immunoconjugate which are less frequently used, but now a days 6 unconjugated antibodies are used in treating the human cancerous cells. Rituximab is one most selling drug in the clinical oncology. This type of monoclonal antibody targets CD20 antigen found on both normal B cells as well as most low-grade as well as higher grade B-cell lymphomas.it is mainly used in treating the non-Hodgkin's B-cell lymphomas and chronic lymphocytic leukemia. The 2nd monoclonal antibody that is more highly effective is trastuzumab, the antibody reacts with 2nd part of the human epidermal growth factors like rituximab, its only effective as single drug agent in induction and maintenance therapy, but it is mainly used as conjunction with chemotherapy for patients with human epidermal growth factor receptor neu (positive) breast cancer.
Modern recombinant techniques had made possible to rapidly produce both chimeric antibodies as well as humanized antibodies. Identifying the surface receptors of the tumor cells leading to development of antibodies and apoptosis of the myeloma cells.
We mainly focused on various ways of monoclonal antibodies producing immunotherapy of cancer by activation directly antibody dependent cellular toxicity, complement activation, blocking of the receptors of cancer cells which are getting the stimuli continuously for the division can be inhibited by blocking the cell cycle pathway by using monoclonal antibodies. Immunotherapy of cancers with monoclonal antibodies by using this various mechanisms helped in curing the severe cancers or myeloma like Non-Hodgkin's lymphomas, ovarian cancer and breast cancer etc. only few myelomas are able to be cured with monoclonal antibodies. We are able to cure only few tumors because of their production is difficult to carryout in selecting cells, transforming and producing hybridoma cells from them is very difficult. Each and every cancer diseases which are treated with monoclonal antibodies are following the same mechanism of action in lysing the cell and causing the death of the cell.
Monoclonal antibodies are useful in treating the tumor cells without causing the any adverse side effects when we are exposed to radiation to lyse the mutated cells and exposing ourselves to various other adverse effects. But by using the various pathways of inhibiting the cancer cells through monoclonal antibodies giving us a new hope in the treating a patient with cancer and also developing the immunity resistance to the body either directly by innate or by adaptive immunity.
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